Manufacture -of cyclic bases de



Patented Apr. 1, i947 "UNITED STATES PATENT OFFICE MANUFACTURE OF .CYCLIC BASES DE- RIVED FRGM ARYLACETONITRILE DE- jarva'rrvns tion of New Jersey No Drawing. Original application March 4, 1942,

Serial No. 433,430. Divided and this application January 3, 1944, Serial No. 516,842. In Great Britain August 12, 1941 .6 Claims.

This invention relates to the manufacture of cyclic bases derived from arylacetonitrile derivatives. It is known that by the condensation of ethylene chlorhydrin with benzyl cyanide OM13- hydroxy-ethyl)-aphenylacetoni-trile is formed. This latter compound on treatment with thionyl chloride gives the corresponding oc(B'-Ch10l'0- ethyl) -a-phenylacetonitrile (cf. Knowles and Cloke, J. American Chemical Society, 1932, 54, 2028).

The introduction of two p-halogenakyl groups into arylacetonitriles has hitherto not been carried out.

According to the present invention ocZzx-biS-(B'- halogenalkyl)-ary1acet0nitriles of the following general formula where R is an aryl group, which may carrysubstituents not interfering with the reaction, and X and Y are B-halogenalkyl groups, are readily prepared. These compounds are transformed into cyclic bases such as piperidine derivatives by condensation with primary amines, subsequent to which the basi nitriles so formed may be converted into the corresponding acids and derivatives thereof.

According to the process of this invention in the manufacture of 4-arylpiperidine-4-nitrile derivatives the aforesaid eta-bis-(c-halogenalky1)- arylacetonitriles are manufactured by condensing an arylacetonitrile in which the reactive methylene group is free, such as benzyl cyanide, with slightly more than two molecular proportions of a fi-halogenalkylvinyl ether, such as fi-chloroethylvinyl ether, in the presence of an alkali metal or an alkali metal compound, such as sodium or sodamide, capable of forming an alkali derivative of the arylacetonitrile. The resulting product is an arm-bis-(B'-vinvyloxyalkyl)-arylacetonitrile, which on mild hydrolysi with an acid reagent splits off the vinyl groups as acetaldehyde and gives the corresponding aZoc-biS-(B'- hydroxyalkyl)-arylacetonitrile. Treatment of the latter compound with any halogenating agent capable of replacing a hydroxyl group with a tives of the acid such as esters, amides, etc, are

formed in known manner.

Vie are aware that British specification No. 501,135 describes the manufacture of piperidine- -nitrile compounds by condensing an arylacetonitrile having a free methylene group in the presence of an agent capable of eliminating [hy drogen halides with certain tertiary amines containing p-halogenalkyl groups.

The following examples illustrate how the process of the present invention may be carried into effect:

1. To a mixture of 17.5 parts by weight of fi-chloroethyl-vinyl ether, 9.6 partsby weight of benzyl cyanide and 100 parts by volume of dry toluene, 6.5 parts by weight of powdered sodamide are added in several portions. The reaction mixture is stirred mechanically and the temperature kept between 30 and 40 C. by gradual addition of the sodamide.

When all the sodamide has been added, the re? action mixture is slowly heated to the boiling point and refluxing continued for 1 /2 hours.

After cooling, water is added and the toluene layer separated. The aqueous part is extracted with ether. The combined etheretoluene extracts are then washed with Water, dried over anhydrous sodium sulphate and evaporated. The residue is distilled in high vacuo. It boils at 135-l40 C./0.2 mm. and is a:a-bis-(p'-viny1oxyethyl)-u-phenylacetonitrile.

Eight parts by Weight. of 0c!oc-blS (,8'ViI1y10Xyethyl) -a.-phenylacetonitrile are added to parts by volume of water at C. with vigorous shaking. 2 parts by volume of concentrated hydrochloric acid (d=l.18) are then added and shaking continued for 10 minutes at 80-90" C. After cooling, the mixture is extracted several times with ether. The combined ether extracts are dried over anhydrous sodium sulphate andevaporated. The residue is recrystallised from a mixture of benzene and petroleum ether ;(.b'oiling 3 point 6080 C.), or from water, and the aux-bis- (fi-hydroxyethyl)-a-phenyl-acetonitrile is obtained in the form of colourless crystals. It melts at 96-98 C.

Six parts by weight of a:u-bis-(;9'-hydroxyethyl)-u-phenyl-acetonitrile are dissolved in 12 parts by weight of diethylaniline. The mixture is cooled to C. and 12 parts by weight of thionyl chloride are added slowly with stirring. When all has been added the mixture is heated on thewater-bath for 45 minutes. After cooling, the dark oily mass is poured on a mixture of ice and dilute hydrochloric acid. After. standing for 15 minutes, the pale brown solid which has separated is extracted with ether, The ether extract is washed with dilute sodium bicarbonate solution and subsequently with water and is dried over anhydrous sodium sulphate. After evaporation of the ether, the residue is recrystallised from petrol ether (boiling point 40-80 C.). .The :a-bis-(,8'-chloroethyl) a phenyl acetonitrile separates in colourless crystals which melt at 52-54 C.

4.8 parts by weight of u:a-bis-( 8-chloroethyl) u-phenyl-acetonitrile are heated with a solution of-2.5 parts by weight of methylamine in 15 parts by volume of absolute alcohol in a sealed tube at 100- 115 C. for 6 hours. The contents of the tube are then washed out with alcohol. The alcohol is evaporated is vacuo and the residue taken up in dilutehydrochloric acid. After-extraction with ether for the removal of non-basic material, the aqueous part is made alkaline with sodium hydroxide and extractedwith ether. The extract is washed with water and dried over anhydrous sodium sulphate; After evaporation of the ether, the residue is distilled in high vacuo. The 1 --methyl-4-phenylpiperidine 4-nitrile obtained boils at 126C./0.2 mm. a

7.5 parts by weight of 1-methyl-4-phenylpiperidine-4-nitrile are heated with 30 parts by volume of concentrated hydrochloric acid (d=1.18) in a pressure bottle at 130 C. for 5 hours. After cooling, the contents of the flask are made alkaline with 4 normal caustic soda. The caustic soda solution after extraction with ether to remove unchanged nitrile is neutralised with dilute hydrochloric acid, when 1-methyl-4-phenylpiperidine- 4-carboxylic acid crystallises out, melting point 308 C. If desired, this acid can be transformed into the corresponding ester by treating it with alcoholic hydrochloric acid in the usual manner. The ethyl 1-methyl-4-phenylpiperidine 4 carboxylate is a liquid boiling at 145 C./1.5 mm. and forms a hydrochloride, melting point 188 C.

2.'To a well stirred solution of 11 parts by weight of o-methylbenzyl cyanide and 39 parts by weight of fl-chloroethyl-vinyl ether in 80 part s by volume of dry toluene are added, parts by weight of powdered sodamide in small portions, so that the temperature is mantained between 30 and 40 C. When all the sodamide has been added the reaction mixture is heated to the boiling point and allowed to reflux for 2 hours. On working up the reaction mixture exactly as described in Example 1 a:a-bis-(B'vinyloxyethyl) uc-(O-tOlYl) -acetonitrile is isolated as an oil which boils at 135-140" C. at 002 mm.

7 parts by weight of'aux-bis- (p'-vinyloxyethyl) a-(o-tolyl)-aceto;1itrile are added with vigorous stirring to 57 parts by weight of water heatedto 90 C. 1.7 parts by volume of concentrated hydrochloric acid are then added'and stirring and heating continued for 10 minutes: "On cooling'a solid separates which after recrystallisation from 4 benzene melts at 101 C. and is am-bis-(B'Jiydroxyethyl) -o(0-tO1y1) -acetonitrile.

To a mixture of 8 parts by weight of mica-bis- (p'-hydroxyethyl) -zx-(O-t0ly1) -acetonitrile and 16 parts by weight of diethylaniline cooled to 0 C. are added slowly with stirring 16 parts by weight of thionyl chloride. The mixture is stirred for a further 30 minutes at 0 C. and then heated on the boiling water bath for a further 45 minutes. The reaction mixture is then treated with excess ice-cold hydrochloric acid and extracted well with ether. The residue left after drying and evaporating the ethereal extract is an oil and distil at tolyl)-piperidine-4-nitrile, the hydrochloride of V which has melting point 280-285 C.

V Hydrolysis of .the above nitrile by heating with concentrated hydrochloric acid at C. for several hours yields 1-methyl-4-(o-t0lyl) -piperidine- 4-carboxylic acid, melting point 305-310" C., the ethylester of which is an oil which boils at C. at 11 mm. pressure.

This application is a divisional application divided out of application Serial No. 433,340, filed March 4, 1942, Patent No. 2,398,575.

We claim: a r

1.A process for the manufacture of 4-arylpiperidine-l-nitrile derivatives which comprises heating an on 2 a-bis- (p'-halogenalkyl) -arylacetonitrile with a primary amine. r

2. A process for the manufacture of 4-arylpiperidine-4-carboxylic acids which comprises,

heating an a oc-blS- (fi' halogenalkyl) -arylacetonitrile with a primary amine and hydrolyzing the product with an acidic reagent.

3. A process of making l-methyl-fl-(o-tolyllheating a2oc-biS-(B'-0h101Oelihy1) -a-phenyl acetonitrile with methylamine. I

6. A process for the manufactureof l-methyL- 4-(o-tolyl) -piperidine-4-nitrile which comprises heating a:a-bis-(fi'-chloroethyl) a (o tolyl) acetonitrile with methylamine.

FRANZ BERGEL. V NATHAN CHADWICK HINDLEY. ALEXANDER LANG MORRISON. HEINRICH RINDERKNECHT.

REFERENCES CITED The following references are of record in'the file of this patent: H t V I UNITED STATES PATENTS 7 Number Name 1 Date. 5 2,167,351 Eisleb fJuly 25, 1939 r "OTHERfREFERENCES Beilstein 4th edition, vol. 9, page 525.

Certificate of Correction Patent No. 2,418,289. April 1, 1947.

FRANZ BERGEL ET AL.

It is hereby certified that errors appear in the above numbered patent requiring correction as follows: In the heading to the printed specification, line 12, for Serial No. 433,430 read Serial No. 433,340; column 3, line 30, for is vacuo read in vacuo; column 4, line 44, claim 3, after the Word and strike out the syllable and hyphen hy-; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 10th day of June, A. D. 1947.

LESLIE FRAZER,

First Assistant Commissioner 0 7 Patents. 

